The histopathology characterizing Alzheimer's disease (AD) involves deposition of amyloid protein (Abeta) in brain parenchyma and cerebral vessel walls, and intraneuronal neurofibrillary tangles. Some hereditary forms of the disease involve peculiar Abeta deposition. In a rare familial disorder, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), Abeta is deposited predominantly in the brain vasculature, causing strokes and early death. Abeta is an aberrant degradation product of an amyloid precursor protein (APP). To date, mutations in the APP gene have been found only in HCHWA-D and in a few families with familial AD (FAD) of early age of onset. The mutations segregate with the disease, indicating a possible role in amyloidogenesis. HCHWA-D and FAD are good models to examine the common features of diseases involving Abeta deposition as well as the causes of the clinicopathological differences between AD, FAD and HCHWA-D. We propose: 1) to screen for mutations in the APP gene in families with early-onset FAD and study the effect of specific mutations on the rate and site of amyloid deposition; 2) to develop an animal model by constructing transgenic mice, in order to test whether mutations in the APP gene cause accelerated Abeta deposition in specific sites of the brain. This model enables analysis of the pathological effect of amyloid deposition, and testing therapeutic approaches.